PROJECT SUMMARY In this Industry-Academic partnership R01 research plan, we propose the development, optimization, and pilot first-in-human evaluation of a bronchoscope-guided microwave ablation (MWA) system for rapid and conformal thermal ablation of early stage pulmonary tumors. Minimally-invasive, image- guided MWA is a cost-effective treatment for thermal destruction of unresectable tumors in the liver, lung, kidney, and other organs. Current MWA technology for pulmonary tumors is limited to a percutaneous approach, which precludes treatment of central tumors and has a high associated risk of pneumothorax. Furthermore, limited intra-procedural feedback and lack of guidance and treatment planning tools places a substantial burden on the physician to precisely position applicators and ensure adequate ablation of the target, while limiting damage to non-targets. Virtual bronchoscopy and navigation, pioneered by Broncus Medical (industrial partner), affords accurate, minimally-invasive access to early-stage pulmonary tumors, with minimal risk of pneumothorax, compared to a percutaneous approach. The team at Kansas State University (academic partner) will develop optimized flexible microwave applicators for delivering localized thermal ablation to pulmonary tumors via a bronchoscopic approach. The proposed MWA devices include antennas with directional control of microwave power deposition for precise ablation of small targets, and will be extensively evaluated with computational models and experimentally, on the benchtop, and in an in vivo animal model. Transient changes in antenna impedance matching will be exploited as a feedback parameter for assessing ablation progress. A machine-learning based treatment planning and guidance platform will be developed and integrated with Broncus? Archimedes planning and virtual bronchoscopy platform to guide the selection of optimal treatment parameters. The integrated system will be translated for first-in- human studies to evaluate the feasibility and safety of bronchoscopically delivering MWA for targeting pulmonary tumors (subaward with University of British Columbia, through Broncus Medical). The central hypothesis of this research is that a bronchoscopic MWA system integrating: (1) applicators with directional control of ablation profiles; (2) impedance-based intra-procedural feedback; and (3) bronchoscopic guidance and treatment planning tools, will afford the safe and effective treatment of localized early-stage pulmonary tumors. The proposed research will lead to the development of an integrated system for bronchoscopic ablation of pulmonary tumors, and its pilot feasibility assessment in human patients. If successful, this work will considerably expand the range of patients with lung tumors that can be treated with a cost-effective, minimally-invasive approach.